Spotlight

Spotlight is a series of 5-minute interviews with an investigator who will explain their rationale for being part of the registry, how it works within their clinic and their aspirations for the registry in the future.

Angela Dispenzieri

Angela Dispenzieri is Professor of Medicine and Professor of Laboratory Medicine and Pathology at The Mayo Clinic, Rochester, Minnesota. Professor Dispenzieri obtained her MD at the Albert Einstein College of Medicine, and later completed her Residency and Fellowship in Hematology and Oncology at The Mayo Clinic College of Medicine. She conducts clinical research and collaborates with both clinicians and basic scientists, with a focus on translational research. Her research interests include a range of plasma cell disorders and systemic amyloidosis.

What was the most important reason for your center to join THAOS?

One of my professional passions is the treatment of amyloidosis. As a hematologist, amyloid light-chain (AL) amyloidosis is my main focus, but part of the role of an amyloidosis expert is the recognition and support of patients with other forms of amyloidosis. Our group at The Mayo Clinic consists of more than 20 clinicians who consider amyloidosis to be a major clinical interest. This includes hematologists, cardiologists, nephrologists, neurologists, and pathologists. As a group, we felt that contributing to THAOS would be an opportunity to help advance the field of TTR amyloidosis.

How is THAOS organized in your clinic?

We have a primary study coordinator who checks the calendars of all the physicians who treat amyloidosis to identify when patients with TTR amyloidosis will be visiting. We also remind our colleagues to call the coordinator when they have a patient with TTR amyloidosis. As a safety check, the primary study coordinator combs the patient records for a diagnosis of TTR amyloidosis and then confirms consent to be entered into the registry. To date, an area where we have been less successful is capturing serial information on patients. As a referral center, patients often come from a distance for initial evaluation and recommendations.

Unfortunately, it is often impractical for patients to return unless they are on an interventional trial; indeed, we have had tremendous success getting return visits from those patients who have enrolled on such programmes.

What do you see as the key value of THAOS for patients and physicians?

The value of THAOS is to afford the description of the disease natural history, as well as investigating genotype / phenotype relationships.

What advantages does THAOS bring to your research?

THAOS has given us the means by which to be more proactive in identifying patients. We have learned more about phenotype / genotype relationships via the registry and are starting to propose more concepts for the use of data from the registry.

What do you hope THAOS will contribute over the next five years?

Hopefully, we will be able to learn more about cardiac biomarkers of this disease. THAOS may also provide us with more detailed information about outcomes among patients who have had liver transplantation.

If you could give one piece of advice to a new THAOS center, what would it be?

Try to be complete in your history and physical examination to achieve a complete dataset (and so that you can get reimbursed for entering information into the database!)

Dr Isabel Conceição

Isabel Conceição is a Consultant in Neurology and Clinical Neurophysiology at Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Lisbon, Portugal. Her clinical practice focuses on neuromuscular outpatient care and clinical neurophysiology, namely electromyography and evoked potentials. She has been the Head of the Familial Amyloid Polyneuropathy outpatient unit, Hospital de Santa Maria, Lisbon, since 2004, where she monitors more than 300 TTR-FAP patients and asymptomatic carriers.

What was the most important reason for your center to join THAOS?

The main reason for my site to join the THAOS registry was the existence of a high number of patients with clinical information organized in a non-structured and non-uniform way.

The longitudinal evaluation in a structured way enables regular follow-up with a strong impact on the perception of the natural history of the disease and of the efficacy of the several therapeutic options.

Also, the opportunity to interact with other THAOS sites scattered worldwide, those that had great experience in approaches to follow-up and evaluation of patients.

How is THAOS organized in your clinic?

The patients followed in our FAP outpatient clinic have different frequencies of follow-up depending on their disease stage: asymptomatic carriers have yearly visits and symptomatic patients visit every 4–6 months.

The patients in our clinic are asked for their informed consent to register their clinical data into the THAOS database. Once informed consent is given, the consultation is conducted according to clinical protocols used in THAOS: global clinical evaluation, neurological evaluation, conduction velocities, and analytical evaluation. These data are not only collected in THAOS but also stored in the patient’s clinical file. We also capture data on cardiologic, ophthalmologic or renal evaluation.

Whenever the patient is lost to follow-up, we establish contact via telephone with the patient or with a family member. This helps us keep the clinical file updated, and, if necessary, discontinue THAOS data collection.

What do you see as the key value of THAOS for patients and physicians?

THAOS has been an extremely useful tool for research, to learn about genotype/ phenotype correlation, and the natural evolution of the disease, as well as the response to treatment.

The interaction between THAOS sites is very important to learn more about other mutations and phenotypes, and has a great impact on our clinical practice.

Participation in this type of study guarantees that clinical data are collected according to standardized clinical questionnaires and ensures the harmonization of clinical information for patients’ benefit.

What do you hope THAOS will contribute over the next 5 years?

THAOS will increase our knowledge on the natural history of the disease and on therapeutic intervention. The rigorous maintenance of the registry will allow us to increase our knowledge of the genotype/phenotype correlation that is not clearly understood in some cases.

Additionally, exchange between experts might lead to changes in the clinical approach, particularly for the management of these patients.

If you could give one piece of advice to a new THAOS center, what would it be?

Although rigorous data collection might appear time consuming, this minimal data set is of the upmost importance to ensure that no information is lost in the global evaluation of patients.

Professor Yukio Ando and Dr Taro Yamashita

Professor Yukio Ando is Professor and Chairman of the Department of Diagnostic Medicine, and Graduate School of Medical Sciences of Kumamoto University, Director of Laboratory Medicine and Vice President of Kumamoto University Hospital, Japan. He is also the Director of The Amyloidosis Research Committee, Research on Intractable Diseases, The Ministry of Health, Labour and Welfare, Japan.

Dr Taro Yamashita, is Project Professor in the Diagnostic Unit for Amyloidosis, Department of Neurology, Kumamoto University Hospital. Professor Ando and Dr Yamashita emphasize the value of THAOS data in improving understanding of the early signs and symptoms of TTR-FAP and the benefit of this information for patients.

What was the most important reason for your center to join THAOS?

There are two prominent reasons to participate in THAOS.

First, we are able to understand current patients’ conditions worldwide through THAOS data. It is crucial that, not only the number of patients, but also the natural course of disease and effects of various treatments are elucidated. Moreover, we can access the latest findings on differences in pathologic condition among regions, the relationship of ATTR to genotype and phenotype, and differences in treatment effects among various therapies, which are expected to be demonstrated. This information will be very important to physicians as they better understand the pathologic condition and use this to determine diagnoses and further treatments.

Second, contrary to the past when liver transplantation was the only option for the treatment, new treatments such as Vyndaqel have been recently introduced. We believe that we will be able to obtain important data about efficacy and safety of these new treatments through THAOS.

How is THAOS organized in your clinic?

At our hospital, although research meetings have been regularly conducted, we make a point of instructing around 50 neurologists in detail about medical examinations before entering THAOS data, as well as measurement methods and assessments such as echocardiography.

Attending THAOS training motivates staff to engage in the treatment. Accelerating data entry has enriched diagnoses and further treatments at our hospital. In order to collect patients’ data completely, we have asked patients to schedule hospital visits in May and November, which are the months that immediately precede the timing of data entry into THAOS at our hospital.

What do you see as the key value of THAOS for patients and physicians?

We collaborate with a patient advocacy group called “Milestone” to plan a trip with patients and their families in autumn, through which we try to understand their various complaints. Patients and their families feel insecure about their everyday life because they frequently feel misunderstood as TTR-FAP is a rare disease occurring only in a handful of people; thanks to the existence of THAOS, patients are able to appreciate that many patients with TTR-FAP exist in Japan and around the world, which helps them to feel secure. We believe that this is a benefit of great value that we can provide for patients.

Also, for medical experts, many findings obtained from THAOS data, such as the relationship between genotype and phenotype, and the natural course of the disease is useful to draw patients’ attention to TTR-FAP. For example, if we are able to accurately tell patients the clinical conditions and symptoms of the disease, they can recognize when they develop symptoms at an early time point. This will encourage patients to tell physicians of their symptoms, which should lead to early diagnosis and early initiation of treatment.

What do you hope THAOS will contribute over the next 5 years?

Although global Phase 3 clinical data of Vyndaqel for 30 months had been presented at scientific meetings, it is important to continue collecting and updating the data for the long term, including the next 5 years. THAOS has value as a source of continuous data collection that can inform the production of guidelines for TTR-FAP.

Since liver transplantation for patients with ATTR has a history of nearly 25 years, a comparison of treatment outcomes between liver transplantation and other treatments is expected.

The introduction of drugs for gene silencing is expected in the future, and a comparison of treatment outcomes between Vyndaqel and liver transplantation could also be discussed. Additionally, safety and tolerability of gene silencing, along with use in a combination with other treatments can also be discussed in the future and will support the appropriate selection of treatments.

Accumulated knowledge of treatment experience with Vyndaqel in patients with severe conditions, the elderly, patients who went through liver transplantation, and patients with non-V30M mutations will be obtained.

Moreover, we are interested in the effect of Vyndaqel beyond its indication, for example on the central nervous system such as cerebral amyloid angiopathy. Currently, most cases are severe and it is considered that Vyndaqel has no effect on cerebral amyloid angiopathy; however, there may be evidence of effect on this disease that are worth investigating.

If you could give one piece of advice to a new THAOS center, what would it be?

It is essential to have a network with people involved worldwide in performing diagnoses and further treatments for TTR-FAP. We hope that all concerned will participate in THAOS, and will then exchange information. This will help improve progress in diagnosing and developing further treatments and studies for TTR-FAP.

We have heard that the process of data entry was a troublesome task, but in our experience this is easy. It may initially seem difficult to enter data but once experience is gained it becomes much easier. To this end, our advice is to examine and entering multiple cases collectively.

By being a part of THAOS, data entered at our hospital is able to be utilized at a global level. The cumulative effect of this is a deepening of understanding of the clinical conditions of this disease and the effects of treatment worldwide. Given these facts, the rate of early diagnosis and treatment is expected to increase. We hope other hospitals will participate in THAOS.

Dr Alejandra González-Duarte

Dr Alejandra González-Duarte works at the Instituto Nacional de Nutrición Salvador Zubirán in Mexico City, where she coordinates a laboratory dedicated to the study of autonomic and small-fiber neuropathy. She is also responsible for a cohort of 80 patients with familial amyloid polyneuropathy. She is keen to stress that smaller centers can contribute a lot to THAOS, because every center has a different population, as such even if they are handling only one or two patients, the information they provide helps to increase our knowledge.

What was the most important reason for your center to join THAOS?

We are a relatively new center for patients with TTR amyloidosis. I began testing probable subjects in 2010, and THAOS was a huge part of this, because it provided the inspiration for doing so. Before 2010, suspected patients were diagnosed by their primary care physician and were not followed-up in a multi-disciplinary fashion, but with the involvement of THAOS we developed new strategies to provide the complete multi-disciplinary care that the patients need.

How is THAOS organized in your clinic?

Patients come to their regular consults as needed, according to their clinical stage and symptoms of the disease. Once in the consultation, for patients already participating in THAOS, we spend some time ensuring that they still want to continue and ask the specific questions that the study requires. For those not involved in THAOS, but who meet the inclusion criteria and are interested, we invite them to a special meeting to talk about it. This serves as the screening visit. For those who do not show up to the follow-up visits, we contact them via telephone to find out why they did not come; sometimes they forget or are not feeling well and they usually reschedule. They very much appreciate the call.

What do you see as the key value that THAOS will provide to patients and physicians?

THAOS has been a great resource for learning more about the disease. It enables us to compare the natural history of the disease throughout different mutations and different countries. For me, it is striking how similar the disease behaves most of the time. That is very important when you are taking care of the patients because most of the time, particularly when the disease is as aggressive as this one, you wonder if you are offering all there is to offer. We are learning from each other´s experience and that has a great impact in what we offer in the clinical practice.

What do you hope THAOS will contribute over the next 5 years?

Having a registry that records all the possible clinical outcomes of the disease is a wonderful source of information that will be very valuable, particularly because it began when there were not many therapeutic options and it registered the natural evolution without modifiers of the disease. It now provides us with information to compare with the many different possibilities that have opened up in the last couple of years. We could not have achieved that alone, we needed a lot of cooperation between centers and countries, and thanks to THAOS we will have the information available faster than we could have imagined.

If you could give one piece of advice to a new THAOS center, what would it be?

Be organized! It is amazing how much information we have from one patient in one visit. It can be exhausting so it is important to do it as close to the visit as possible. New, smaller centers can contribute a lot to THAOS, because every center has a different population, so even if they are handling only one or two patients, those are invaluable for the global purpose of the study.

Dr Mathew Maurer

Columbia University, New York, USA was the first center to join THAOS. Here, Dr Mathew Maurer, Director of the Clinical Cardiovascular Research Laboratory for the Elderly at Columbia University, explains how THAOS is incorporated into his clinical practice and shares his thoughts on the value of being involved with the database.

What was the most important reason for your center to join THAOS?

THAOS, by exploring the genotype and phenotype interactions in a large, international, representative, heterogeneous cohort of patients will allow us to advance our understanding and better inform patients and their loved ones as to what they are going to face in the future. Until we have a better understanding of all aspects of the condition it is going to be hard to evaluate the efficacy of potential therapies that are on the horizon.

How is THAOS organized at your clinic?

At Columbia, we have over 50 patients registered in THAOS. Patients are referred for advanced care and are seen by a multidisciplinary team including a cardiologist and a nurse practitioner
initially, and other health care providers when required. All patients are provided with routine clinical care and those with TTR-cardiac amyloidosis who are clinically stable are seen every 3–4 months. We see them even if they are feeling well as it does not take much for these patients to deteriorate with regards to their heart failure. Part of the routine clinical evaluation includes collecting data on the patients’ signs and symptoms, concerns and complaints, physical examination findings, laboratory data and the results of any imaging. All of this information is placed in the THAOS registry. None of the data are collected specifically for THAOS, this is all information that is clinically available and provided for the patient. This obviously can vary from site to site.

At Columbia, we have a dedicated member of staff who is aware of patient appointments and is provided with reminders by the THAOS program, so when a patient comes in for a follow-up visit their data are placed into THAOS. The THAOS system is easy to use as it does not distract from the regular practice of providing clinical care. THAOS is a seamless add-on.

There is a vast amount of information that could be collected in THAOS. However, there is a ‘minimum data set’ that needs to be recorded. It is important to remember that amyloidosis is a multi-system disorder and as such care providers for patients should be encouraged to branch out of their specialty domain and ensure they are able to assess other organ systems. For example, as a cardiologist I need to
be able to perform succinct neurological examinations in order to identify if the patient who has mainly cardiac signs and symptoms also has any concomitant neurological or neuropathic findings.

What do you see as the key values of THAOS for patients and physicians?

THAOS not only provides data on the condition itself but also provides emerging data on practice patterns across different countries. As globalization occurs and healthcare becomes more globally delivered, THAOS provides the opportunity for colleagues from different centers to learn from each other. It is important that patients accrued in THAOS are followed up over time in order to define the natural history of the condition. Although these data are no doubt already collected, THAOS is able to provide more depth and breadth than any individual practitioner or single center’s experience.

What do you hope THAOS will contribute over the next 5 years?

Over the next 5–10 years, I believe THAOS will show a trend towards an increased recognition of wild type cardiac or senile cardiac amyloidosis. With an ageing population, this is a cohort that is currently one of the smaller subsets in THAOS but is likely to grow. It will be interesting to see how effective therapies may emerge as well. Above all, THAOS will be a stepping stone for high-quality, clinical investigations that will most importantly accomplish the goals of patients living longer and feeling better.

If you could give one piece of advice to a new THAOS center, what would it be?

My advice to others in relation to starting to use THAOS is to remember to ask questions if you are uncertain of things. It is in the interest of everyone that the data collected in THAOS are as high quality and as robust as possible. It is also important to remember why you want to engage in THAOS; you have a keen scientific interest and a strong commitment to patients. THAOS is not a labor that is financially remunerable; we are not doing this to make money, we are doing this to advance the care of our patients and to provide a greater understanding of this condition. It is a ‘labor of love’.

Professor Violaine Planté-Bordeneuve

Violaine Planté-Bordeneuve holds a position as a Professor of Neurology at the Department of Neurology, CHU Henri Mondor, Créteil, France where she set up a multidisciplinary network dedicated to amyloidosis, recently labelled reference center. Her main research interests include neurogenetics, neuromuscular disorders, particularly inflammatory neuropathies and inherited neuropathies. In the field of transthyretin familial amyloid polyneuropathy her works covered genotypic–phenotypic correlations, genetic epidemiology and therapeutic approaches.

Department of Neurology,CHU Henri Mondor, Créteil, France

Department of Neurology,CHU Henri Mondor, Créteil, France

How is THAOS organized at your clinic?

Each week we hold a clinic for patients with ATTR and I carefully evaluate the neurologic aspects of their disease. At my centre, we are organised within a multidisciplinary network and patients will typically also receive cardiologic evaluation on the same day. The following day, a dedicated member of the team will upload all data collected at the clinic to THAOS ready for my review and signature. THAOS prompts us to upload data on a regular basis and we rely on the database for accurate follow up of our patients. We know that by using THAOS as our guide, we will achieve appropriate follow-up of all aspects of the disease for every patient.

What do you see as the key values of THAOS for patients and physicians?

In addition to supporting accuracy of follow up for each patient we monitor, THAOS ensures that we pay attention to other manifestations of this systemic disease. As neurologists, we tend to see only the neurologic aspects of disease. THAOS is helpful in ensuring that we gather a global overview of a patient’s disease. This is important for ensuring that we deliver the best care for each individual patient. Beyond this, THAOS has been important in helping us to develop new tools for disease assessment such as cardiac scintigraphy.

How do you believe THAOS has shaped understanding of ATTR and clinical practice?

THAOS has offered important input into our understanding of ATTR. A wealth of data has been collected in THAOS that helps improve understanding of the phenotype and genotype of the disease in different areas across the world. We have learned a tremendous amount about different aspects of the disease; cardiologic aspects in particular are now far better delineated. THAOS helped us to understand ATTR as a systemic disease, not just a neurologic disease as it was historically known. Beyond this, as Investigators we have also learnt a lot from each other and THAOS has facilitated this by increasing interaction between different physicians in different specialities.

What advantages does THAOS bring to your research?

Using the THAOS database, it is easy for us to extract information on different aspects of our patient population. This can then be covered in educational presentations or used to answer questions we have in our clinical research. For example, as we know, misdiagnosis is an important challenge we face with ATTR. Through analysing the data in THAOS on subjects who have been misdiagnosed I have been able to prepare presentations that provide accurate information on patient groups in which ATTR should be.

What do you hope THAOS will contribute over the next five years?

Today, we better understand the phenotype and genotypes of ATTR, and this is in large part thanks to THAOS. Moving forwards, I think that THAOS can really support us, both in improving follow up of these patients and in understanding how different aspects of this systemic disease progress.I believe that THAOS will help us to understand how the disease course varies within different groups of patients and will help us to not only understand the natural history according to genotype and phenotype, but also the impact that treatment has on patients in the long term.

If you could give one piece of advice to a new THAOS center, what would it be?

I would strongly recommend that physicians set up a network between neurologists, cardiologists and other specialities in their hospital to ensure that all aspects of a patient’s disease are being fully assessed. We must consider this disease as truly systemic and must follow all aspects of their disease, at least every year. We must be prepared to use the information that we gather and modify treatments if necessary in order to deliver the best possible care for our patients.

Dr Arnt Kristen

Arnt Kristen works as a Senior Physician at the Heidelberg Heart Center and the Heidelberg Amyloidosis Center at the University of Heidelberg, Germany. His scientific and clinical focus is on cardiomyopathies and rare diseases, including the management and treatment of these disorders through approaches such as heart transplantation. Dr Kristen’s particular interests are cardiac amyloidosis and the field of interventional cardiology.

How is THAOS organized at your clinic?

The THAOS registry is mainly based in the Department of Cardiology, Heidelberg Amyloidosis Center, given the highest proportion of our patients with wild-type TTR amyloidosis first present with cardiac symptoms. During routine assessments and visits at our center, all patients that satisfy the inclusion and exclusion criteria will be informed of the importance of the THAOS registry and asked for permission to be included in the dataset.

What do you see as the key values of THAOS for patients and physicians?

THAOS is a unique opportunity to collect extensive data across the various fields of TTR amyloidosis. Through using these data, vital information will be available on the heterogeneous presentation of TTR amyloidosis and our patients will benefit from the overall improvement in knowledge of this rare disease. Additionally, there is the potential to establish diagnostic algorithms for TTR amyloidosis.

What advantages does THAOS bring to your research?

THAOS allows me to access a huge database detailing different aspects of TTR amyloidosis. Currently, I am analyzing the prognostic use of cardiac biomarkers in a large cohort of patients with different genotypes and phenotypes of TTR amyloidosis; a single center is not capable of collecting such volumes of patient data.

What do you hope THAOS will contribute over the next five years?

Providing further information, not only on the natural course of TTR amyloidosis, but also on predictors of outcome.

If you could give one piece of advice to a new THAOS center, what would it be?

New centers should make efforts to collect complete datasets including neurologic, cardiologic and laboratorybased assessments. Moreover, they should actively encourage their patients to attend their follow-up visits.

Dr Fabio Barroso

Fabio Barroso is a Neurologist at the Institute for Neurological Research Raul Carrea (FLENI), in Buenos Aires, Argentina. His main areas of expertise include neuromuscular diseases and neurophysiology, with a special interest in hereditary amyloid neuropathies. Dr Barroso has been the lead PI in a number of trials on familial amyloid neuropathy. Since 2010 he has collaborated with the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry and served as an important member of the scientific board.

How is THAOS organized at your clinic?

FLENI is a specialty hospital for neurological and neurosurgical disorders. Many of our patients come from all over the country seeking specialized care of rare, often undiagnosed, afflictions. Peripheral neuropathies are among such disorders. In our dedicated clinic for peripheral neuropathy cases, we have diagnosed over 100 TTR amyloidosis cases over the past 10 years. With the aim of increasing our understanding of the natural course of the disease, improve our detection strategies and our ability to measure the effects of treatment, we offer patients affected by TTR amyloidosis a follow up program which includes clinical assessments, neurophysiological testing, QST testing and autonomic testing on a periodic basis.

What studies and investigations are you interested in conducting using THAOS data?

We are interested in the clinical aspects of the neuropathy of TTR amyloidosis, particularly its impact on the autonomic nervous system. We also have an interest in studies that correlate clinical, functional and histological assessments of TTR neuropathy.

What do you believe THAOS has contributed to the field of ATTR research and consequently to improvements in patient care over the past decade?

THAOS provide us a framework to collaborate with and learn from many experts in the field of amyloidosis. Furthermore, the volume of clinical data collected in THAOS provides a unique opportunity to understand aspects of the disease that would be impossible to acquire from a single institution’s experience, due its low prevalence. For instance, genotype–phenotype correlations, and characterization of the clinical profile in subjects with uncommon mutations.

Additionally, the enthusiastic participation of many investigators from many countries has opened the landscape of the disease in ways we did not envisioned 10 years ago. Our perception of the disease has changed from one that saw TTR-FAP as a disease isolated to a handful of ‘endemic’ regions to one of a widely disseminated, although still rare, disease.

How do you hope to see THAOS develop over the next decade?

When THAOS was conceived, relatively few clinicians and investigators around the world were interested in TTR amyloidosis. As the number of professionals interested in TTR amyloidosis grows, our scope of the disease expands, and new treatments for it become available, the registry will probably need to incorporate new data categories to fulfil its purpose of improve our understanding of the disease.

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